6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide

HRID 246229Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 246229
[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22](Br)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([Sn](CCCC)(CCCC)CCCC)=[N:40][N:41]2[CH3:44])=[CH:37][CH:36]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:39]4[C:38]5[C:42](=[CH:43][C:35]([F:34])=[CH:36][CH:37]=5)[N:41]([CH3:44])[N:40]=4)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Komponenten

6

Edukt 2

HCID 712803076-fluoro-1-methyl-3-(tributylstannyl)-1H-indazoleHCID 866779622-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide

Produkt 1

HCID 712860862-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amideAusbeute 68,3 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

In a 40 ml vial containing 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (1.32 g, 2.49 mmol) was added a solution of 6-fluoro-1-methyl-3-tributylstannyl-1H-indazole (1.20 g, 2.73 mmol) in DMF (25 ml). The vial was backfilled with nitrogen and tetrakis(triphenylphosphine)palladium (0) (159 mg, 0.14 mmol) and copper (I) iodide (107 mg, 0.56 mmol) were added. Again the vial was backfilled with nitrogen, then sealed and the reaction mixture was stirred in a heating block at 80° C. for 4 h. The reaction mixture was cooled to room temperature diluted with EtOAc/hexanes (100/30 ml) and washed with water (100 ml). The aqueous layer was extracted with EtOAc/hexanes (100/30 ml). The combined organic layers were washed with brine then dried over MgSO4, filtered, and concentrated. The crude was purified by flash chromatography (120 g Analogix) with 20% to 100% EtOAc in hexanes. The approriate fractions were combined and concentrated to yield 1.02 g (62%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a light yellow solid. LC-MS (M+H)+=600.

Aufarbeitung

  1. additionwere added
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. washwashed with water (100 ml)
  5. extractionThe aqueous layer was extracted with EtOAc/hexanes (100/30 ml)
  6. washThe combined organic layers were washed with brine
  7. dry with materialthen dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude was purified by flash chromatography (120 g Analogix) with 20% to 100% EtOAc in hexanes
  11. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-ddc60f172724478199e983661ba23508
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

Notizen zur Reaktion

Wird geladen…